Site-specific percutaneous absorption of methyl salicylate and VX in domestic swine

• Published in: Journal of applied toxicology Vol. 22; no. 3; pp. 141 - 148
• Main Authors: Duncan, E. J. Scott, Brown, April, Lundy, Paul, Sawyer, Thomas W., Hamilton, Murray, Hill, Ira, Conley, John D.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-05-2002; Wiley
• Subjects: Abdomen; absorption; Administration, Cutaneous; Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; chemical warfare agents; Chemical Warfare Agents - pharmacokinetics; Cholinesterases - blood; domestic swine model; Ear; Inguinal Canal; Male; Medical sciences; methyl salicylate; Models, Animal; Organothiophosphorus Compounds - administration & dosage; Organothiophosphorus Compounds - pharmacokinetics; percutaneous absorption; Perineum; protective clothing; Salicylates - administration & dosage; Salicylates - pharmacokinetics; Skin - drug effects; Skin - metabolism; Swine - physiology; Toxicology; Various organic compounds; Animal model; Organic thiophosphonate; Enzyme; Esterases; Cholinesterase; Carboxylic ester hydrolases; Pig; Percutaneous route; Site specificity; Toxicokinetics; Chemical warfare agent; Vertebrata; Mammalia; Absorption; Enzymatic activity; Hydrolases; Organophosphorus compounds; Skin; Artiodactyla; Kinetics; Mechanism of action; Ungulata; Topical administration
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.838

The site specificity of the percutaneous absorption of methyl salicylate (MeS) and the organophosphate nerve agent VX (O‐ethyl S‐(2‐diisopropylaminoethyl) methylphosphonothioate) was examined in anaesthetized domestic swine that were fully instrumented for physiological endpoints. Four different anatomical sites (ear, perineum, inguinal crease and epigastrium) were exposed to the MeS and the serum levels were measured over a 6‐h time period. The dose absorbed at the ear region was 11 μg cm−2 with an initial flux of 0.063 μg cm−2min−1, whereas at the epigastrium region the dose absorbed was 3 μg cm−2 with an initial flux of 0.025 μg cm−2min−1. For this reason further studies were carried out with VX on the ear and the epigastrium only. In animals treated with agent on the epigastrium, blood cholinesterase (ChE) activity began to drop 90 min after application and continued to decline at a constant rate for the remainder of the experiment to ca. 25% of awake control activity. At this time there were negligible signs of poisoning and the medical prognosis was judged to be good. In contrast, the ChE activity in animals receiving VX on the ear decreased to 25% of awake control values within 45 min and levelled out at 5–6% by 120 min. Clinical signs of VX poisoning paralleled the ChE inhibition, progressing in severity over the duration of the exposure. It was judged that these animals would not survive. The dramatic site dependence of agent absorption leading to vastly different toxicological endpoints demonstrated in this model system has important ramifications for chemical protective suit development, threat assessment, medical countermeasures and contamination control protocols. Copyright © 2002 Crown in the right of Canada. Published by John Wiley & Sons, Ltd.